Endocochlear potential (EP) (> 80 mV) is a requisite for normal sound transduction. The significance of EP to normal hearing is underpinned by the evidence that in most animal models of age-related hearing loss the hearing threshold/sensitivity is directly related to EP at ~1 dB/mV. Recent reports have identified a novel K+ channel, (TWIK-1 or KCNK1), with unknown functions in the inner ear that are expressed at high densities at the apical membrane of marginal cells (MCs). Because the TWIK-1 is non-voltage-gated, it should serve as a background current to promote high K+ throughput. We have also identified and cloned an inner ear lateral wall-specific K+ channel, MERG1a, which is poised in the strial vascularis (StV) to contribute towards K+ flux. Last, it is thought that a major channel involved in the high throughput of outward K+ movement across the intermediate cells (ICs) to generate EP is the Kir4.1 channel. Paradoxically, Kir4.1 is an inward rectifying K+ channels (Kir). Moreover, we have also identified other inward rectifier channel subtypes, Kir4.2 and Kir5.1 that may form functional heteromultimers with Kir4.1 in the StV. We hypothesize that EP is produced and maintained by a cadre of K+ channels in the apical membrane of ICs and MCs as well as basolateral Cl- channels in conjunction with NKCC1 and Na+/K+ ATPase. We will determine the properties of K+ and Cl- conductances in their native settings in cells of the StV. In addition, we will clone and examine cochlear lateral wall (LW)-specific K+ and Cl- channels using a variety of molecular biological, biochemical and functional techniques. The channel properties will be studied in detail in vitro. Last, we will identify the functional role of the channels, in vivo, by crippling the functions of the channels using cell-specific dominant-negative (DN) strategies in the StV in mice. Collectively, these studies will substantially expand our understanding of the specific functions of individual K+ and Cl- channels, as well as the different cell types in the StV, and how they work together to mediate EP and transepithelial ion transport processes in vivo.